Novel Polymorphs Of Azabicyclohexane

ABSTRACT

The invention provides polymorphic crystalline forms of acid addition salts of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane designated as polymorph form A, polymorph form B and polymorph form C, where polymorph form A is more thermodynamically stable than the other forms, methods for preparing and using such polymorph forms and pharmaceutical compositions containing such polymorph forms.

This application claims priority to U.S. patent application Ser. No.10/920,748, filed Aug. 18, 2004, which is converted to a provisionalapplication.

Salts of the (−) isomer of phenyl azabicyclohexane having the formula

are known for use in treating depression. As set forth in Lippa et al.,U.S. Pat. No. 6,372,919, the compound of formula I whose chemical nameis (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in its (+)isomeric form has been found to have potent anti-depressive activity.

While the azabicyclohexanes of formula I have been prepared as describedin various U.S. patents such as U.S. Pat. Nos. 4,231,935, 4,131,611,4,435,419, 4,118,417 and 4,196,120, these compounds were prepared inracemic form. In the procedure of Lippa et al., U.S. Pat. No. 6,372,919,the (+) optical antipode was produced as a mixture of various isomericpolymorphic forms which heretofore have been unrecognized. A purecrystalline form of the (+) isomer of the compound of formula I is ofparticular importance since it could be formulated into variouspharmaceutical dosage forms such as for example tablets or capsules fortreatment of patients. Variations in crystal structure of apharmaceutical drug substance are known to affect the dissolution,manufacture, stability and bioavailability of a pharmaceutical drugproduct, particularly in solid oral dosage forms. Therefore it isimportant to produce the (+) isomer of the compound of formula I in apure form comprising a single thermodynamically stable crystalstructure.

SUMMARY OF INVENTION

In accordance with this invention, it has been discovered that the (+)optical antipode of the compound of formula I as prepared in Lippa etal., U.S. Pat. No. 6,372,919 exists as a mixture of two crystallinepolymorphic structures, one being the hemi-hydrate form, which isdesignated as polymorph form A, and the other being the anhydrous form,which is designated as polymorph form B. A dehydrated form designated aspolymorph form C has also been found. When the (+) optical antipode ofthe compound of formula I is produced by prior art procedures, it hasbeen found that it was produced as a mixture of polymorph form A andpolymorph form B which do not readily separate into their purepolymorphic crystalline forms.

In accordance with this invention, a method of forming these polymorphsas pure independent polymorph forms has been discovered. In addition wehave found that the polymorph form A of the (+) optical antipode of thecompound of formula I in its pure crystalline structure produced inaccordance with this invention is a thermodynamically stable polymorphform. Therefore, form A is the preferred crystalline form of the (+)optical antipode of the acid addition salt of the compound of formula Ifor formulation into pharmaceutical drug products.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with this invention, it has been discovered that the (+)optical antipode of acid addition salts of the compound of formula Iexists in three different crystalline polymorphic forms designated aspolymorph form A, polymorph form B and polymorph form C and thatpolymorph form A, which is the hemi-hydrate form, is a thermodynamicallystable form.

Polymorph form A may be characterized as the hemi-hydrate of acidaddition salts of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.It is the hemi-hydrate crystalline form, which uniquely characterizespolymorph form A from polymorph form B and polymorph form C of acidaddition salts of the compound of formula I. Polymorph form B andpolymorph form C of acid addition salts of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane do not exist ashemi-hydrates.

The polymorphs of acid addition salts of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may also becharacterized by their X-ray powder diffraction patterns (XRPD) and/ortheir Raman spectroscopy peaks. With respect to X-ray powderdiffraction, the relative intensities of the X-ray powder diffractionpeaks of a given polymorph may vary depending upon the crystal size ofthe polymorph used to determine the pattern. This is a phenomenon ofpreferred orientation. Preferred orientation is caused by the morphologyof crystals. In this case, the XRPD analysis should be carried out withthe sample spinning in the sample holder during XRPD analysis to reducethe preferred orientation effects. Samples for XPRD analysis fordetermination of the presence and nature of their polymorph status inaccordance with this invention should be lightly ground and/or sieved toa crystal size of from about 10 to 40 microns for XPRD analysis.

A Bragg-Brentano instrument, which includes the Shimadzu system, usedfor the X-ray powder diffraction pattern measurements reported herein,gives a systematic peak shift (all peaks can be shifted at a given “°2θ”angle) which result from sample preparation errors as described in Chenet al.; J Pharmaceutical and Biomedical Analysis, 2001; 26, 63.Therefore, any “°2θ” angle reading of a peak value is subject to anerror of about (±) 0.2°.

The X-ray powder diffraction pattern (XRPD) analyses of polymorph formsA, B and C were performed with a Shimadzu XRD-6000 X-ray powderdiffractometer using Cu Ka radiation. In this procedure the compound asa hydrochloride salt was loaded onto the machine as a crystallinepowder. The instrument was equipped with a long fine focus X-ray tube.The tube voltage and amperage were set to 40 kV and 40 mA, respectively.The divergence and scattering slits were set at 1° and the receivingslit was set at 0.15 mm. Diffracted radiation was detected by a Nalscintillation detector. A theta-two theta continuous scan at 3°/min (0.4sec/0.02° step) from 2.5 to 40 °2θ was used. A silicon standard wasanalyzed to check the instrument alignment. Data were collected andanalyzed using XRD-6000 v. 4.1.

The following Table 1 shows the peaks of the X-ray powder diffractionpattern of purified polymorph form A of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystalsize of from about 10 to 40 microns. This pattern is given in terms ofthe “°2θ” angles of the peaks subject to the angle error set forthabove. With respect to the percent value of relative intensity (I/lo)given in Table 1, represents the value of the maximum peak determined byXRPD for the sample for ad “°2θ” angles and I represents the value forthe intensity of a peak measured at a given “°2θ” angle”. The angle“°2θ” is a diffraction angle which is the angle between the incidentX-rays and the diffracted X-rays. The values for the relativeintensities for a given peak set forth in percent and the “°2θ” angleswhere said peaks occur are given in Table 1 below.

TABLE 1 XRPD Peaks (°2θ) and Relative Intensities (I/Io) for PolymorphForm A Form A °2θ I/Io 4.55 25 9.10 15 13.65 6 17.14 60 17.85 11 18.2423 18.49 14 19.27 14 19.62 22 21.74 15 21.96 100 22.24 12 23.01 7 24.5243 24.79 10 26.74 52 27.44 11 27.63 17 28.36 16 28.48 26 29.00 14 29.2019 29.40 27 29.57 27 30.24 18 31.01 13 31.62 17 32.20 24 32.93 12 33.429 34.24 6 35.08 15 35.65 16 36.31 14 37.11 26 37.78 9 39.85 9

The following Table 2 shows the peaks of the X-ray powder diffractionpattern of purified polymorph form B of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystalsize of from about 10 to 40 microns. The values for the relativeintensities for a given peak set forth in percent and the “°2θ” angleswhere said peaks occur for polymorph form B of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystalsize of about 10 to 40 microns are given in Table 2 below.

TABLE 2 XRPD Peaks (°2θ) and Relative Intensities (I/Io) for PolymorphForm B Form B °2θ I/Io 10.50 6 13.34 12 15.58 42 17.12 6 17.36 8 17.5226 18.21 11 20.40 7 21.35 97 21.61 17 21.93 11 22.64 6 23.04 79 24.09 624.52 14 25.43 96 26.24 53 26.36 73 26.75 11 26.88 7 27.44 6 27.94 1228.36 20 28.54 30 29.39 10 29.72 9 30.07 7 30.58 8 30.72 100 31.07 1431.38 12 31.55 7 31.78 12 32.14 10 32.31 7 32.80 7 32.95 6 33.45 4433.74 12 35.25 10 35.40 12 35.58 9 36.75 8 37.55 18 39.01 15 39.22 739.37 7 39.86 11

The following Table 3 shows the peaks of the X-ray powder diffractionpattern of purified polymorph form C of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystalsize of from about 10 to 40 microns. The values for the relativeintensities for a given peak set forth in percent and the “°2θ” angleswhere said peaks occur for polymorph form C of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystalsize of about 10 to 40 microns are given in Table 3 below.

TABLE 3 XRPD Peaks (°2θ) and Relative Intensities (I/Io) for PolymorphForm C Form C °2θ I/Io 5.46 6 5.66 20 6.37 6 7.26 6 8.75 6 13.34 2513.94 11 15.65 7 16.26 7 17.01 8 17.38 9 17.64 83 17.92 15 18.23 4019.08 7 19.38 46 19.86 20 20.07 100 21.16 17 21.32 94 21.64 37 22.42 2522.70 12 22.97 70 23.31 6 24.09 15 24.86 94 25.24 32 25.38 49 26.12 1326.32 90 26.87 18 27.21 39 27.90 54 28.14 8 28.56 32 28.74 17 29.20 629.72 6 29.92 26 30.54 13 30.72 19 30.96 31 31.42 7 31.68 11 31.80 1531.97 6 32.43 21 33.26 12 33.40 15 33.64 25 33.84 18 34.11 15 34.70 1135.07 8 35.64 11 35.91 8 36.09 21 37.80 12 38.06 6 38.17 6 39.04 6 39.238 39.77 7

However, there are key major peaks at given angles in these X-ray powderdiffraction patterns which are unique to each given polymorph form.These peaks are present in the XRPD patterns of each of the polymorphforms having a crystal size of about 10 to 40 microns. Any of thesemajor peaks, either alone or in any distinguishing combination, aresufficient to distinguish one of the polymorph forms from the other twopolymorph forms. For polymorph form A, the “°2θ” angles of these majorpeaks which characterize polymorph form A, subject to the error setforth above, are as follows:

-   -   17.14;    -   19.62;    -   21.96;    -   24.52;        -   and    -   26.74.        Any of these major peaks, either alone or in any distinguishing        combination, are sufficient to distinguish polymorph form A from        the other two polymorph forms.

Also, there are key major peaks at given angles in the XRPD of polymorphform B which are unique to polymorph form B as the hydrochloride salthaving a crystal size of about 10 to 40 microns that are typicallypresent in the XRPD pattern of polymorph form B as the hydrochloridesalt irrespective of the particle size. Any of these major peaks, eitheralone or in any distinguishing combination, are sufficient todistinguish polymorph form B from the other two polymorph forms. Forpolymorph form B, the “°2θ” angles of these major peaks whichcharacterize polymorph form B, subject to the error set forth above, areas follows:

-   -   15.58;    -   17.52;    -   21.35;    -   23.04;    -   25.43;        -   and    -   30.72.

Also, there are key major peaks at given angles in the XRPD of polymorphform C which are unique to polymorph form C as the hydrochloride salt,having a crystal size of about 10 to 40 microns, that are typicallypresent in the XRPD pattern of polymorph form C as a hydrochloride saltirrespective of the particle size. Any of these major peaks, eitheralone or in any distinguishing combination, are sufficient todistinguish polymorph form C from the other two polymorph forms. Forpolymorph form C, the “°2θ” angles of these major peaks whichcharacterize polymorph form C, subject to the error set forth above, areas follows:

-   -   13.34;    -   17.64;    -   20.07;    -   21.32;    -   22.97;    -   24.86;    -   26.32;        -   and    -   27.90.

Another method of characterizing the three polymorphs of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is through Ramanspectroscopy. The procedure for carrying out Raman Spectroscopy isdescribed on pages 260-275 of Skoog and West, Principles of InstrumentalAnalysis (2nd Ed.); Saunders College, Philadelphia (1980).

Briefly, Raman spectra were obtained using a FT-Raman 960 (or 860)spectrometer (Thermo Nicolet) interfaced to an 860 FT-IR. Thisspectrometer uses an excitation wavelength of 1064 nm. Approximately0.912 W of Nd:YV0₄ laser power was used to irradiate the samples. TheRaman spectra were measured with an indium gallium arsenide (InGaAs)detector. The samples were pressed into pellets for analysis. A total of128 sample scans were collected from 3600 or 3700 −98 cm⁻¹ at a spectralresolution of about (±) 4 cm⁻¹, using Happ-Genzel apodization.Wavelength calibration was performed using sulfur and cyclohexane. TheRaman spectra peak positions given below in wavenumbers (cm⁻¹) for thepurified polymorph forms A, B and C of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are subject to anerror of about (±) 4 cm⁻¹.

The Raman spectra peak positions in wavenumbers (cm⁻¹) for polymorphform A of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are given in Table4.

TABLE 4 Raman Peak Listing for Polymorph Form A (peaks >400 cm⁻¹) PeakPositions In Wavenumbers (cm⁻¹) Form A 436 479 534 549 646 691 680 762812 836 892 921 959 982 998 1030 1056 1099 1122 1135 1189 1229 1274 13091338 1366 1393 1453 1484 1557 1597 2890 2969 2982 3017 3046 3064

The Raman spectra peak positions in wavenumbers (cm⁻¹) for polymorphform B of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are listed in Table5.

TABLE 5 Raman Peak Listing for Polymorph Form B (peaks >400 cm⁻¹) PeakPositions In Wavenumbers (cm⁻¹) Form A 418 446 478 533 648 676 686 767825 852 895 964 979 1031 1054 1070 1099 1136 1189 1245 1278 1309 13431380 1398 1456 1483 1557 1593 2895 2963 2993 3027 3066

The Raman spectra peak positions in wavenumbers (cm⁻¹) for polymorphform C of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are given in Table6.

TABLE 6 Raman Peak Listing for Polymorph Form C (peaks >400 cm⁻¹) PeakPositions In Wavenumbers (cm⁻¹) Form C 441 474 532 648 674 690 767 811826 856 895 970 1031 1059 1094 1122 1137 1189 1228 1246 1266 1279 13091343 1398 1456 1471 1557 1595 2900 2966 2992 3048 3070

Table 4, Table 5 and Table 6 provide the complete patterns of the Ramanpeak positions with respect to the hydrochloride salts of polymorphforms A, B and C respectively. However, there are certain key peaks,within these patterns, which are unique to each of the hydrochloridesalts of these polymorphs. Any of these key peaks, either alone or inany distinguishing combination, are sufficient to distinguish one of thepolymorph forms from the other two polymorph forms. These peakpositions, expressed in wavenumbers (cm⁻¹) for the hydrochloride salt ofpolymorph form A are:

Peak Positions in Wavenumbers (cm⁻¹) for Polymorph Form A

-   -   762;    -   636;    -   921;    -   959;    -   1393;    -   1597;    -   2890;    -   2982;        -   and    -   3064.        Any of these key peaks, either alone or in any distinguishing        combination, are sufficient to distinguish polymorph form A from        the other two polymorph forms

The characterizing peak positions expressed in wavenumbers (cm⁻¹) forthe hydrochloride salt of polymorph form B are:

Peak Positions in Wavenumbers (cm⁻¹) for Polymorph Form B

-   -   1245;    -   1380;    -   2963;    -   2993;    -   3027;        -   and    -   3066.        Any of these key peaks, either alone or in any distinguishing        combination, are sufficient to distinguish polymorph form B from        the other two polymorph forms.

The characterizing peak positions expressed in wavenumbers (cm⁻¹) forthe hydrochloride salt of polymorph form C are:

Peak Positions in Wavenumbers (cm⁻¹) for Polymorph Form C

-   -   1059;    -   1094;    -   1266;    -   1343;    -   1595;    -   2900;    -   2966;        -   and    -   3070.        Any of these key peaks, either alone or in any distinguishing        combination, are sufficient to distinguish polymorph form C from        the other two polymorph forms

In accordance with this invention, each of the crystalline polymorphforms of the acid addition salt(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can be obtainedsubstantially free of its other enantlomeric, geometric and polymorphicisomeric forms. The term “substantially free” of its other enantiomeric,geometric and polymorphic isomeric forms designates that the crystallinematerial is at least about 95% by weight pure in that it contains nomore than about 5% w/w of its other enantiomeric, geometric andpolymorphic isomeric forms.

In the past, preparation of acid addition salts of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.]hexane has resulted in amixture of the A and B polymorph forms. This mixture constituted anapproximately 50% by weight mixture of each polymorph which could not beeasily separated. In addition, it has been found that there was someinter-conversion of polymorph forms A and B upon standing at ambienttemperature or inter-conversion, upon heating, of this 50% mixture toform a mixture of polymorph forms A, B and C. However, these mixturescould not be easily separated. Therefore, the purified isomeric forms ofthese individual polymorph forms substantially free of its otherenantiomeric, geometric and polymorphic isomeric forms could not beobtained.

In accordance with this invention, it has been discovered that polymorphforms A, B and C of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, particularly ashydrochloride acid addition salts, can each be prepared substantiallyfree of its other enantiomeric, geometric and polymorphic isomeric formsthrough re-crystallization of a mixture of the A and B polymorph formsproduced in accordance with prior art procedures. Depending upon theparticular solvent, conditions and concentrations of materials utilizedto re-crystallize the mixture of polymorph forms A and B, one canselectively produce the desired polymorph form of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, substantially freeof its other enantiomeric, geometric and polymorphic isomers.

In preparing polymorph forms A and B substantially free of otherpolymorph forms, crystallization from a mixture of A and B is generallyutilized. However, the crystallization technique with regard toproducing each of these polymorph forms substantially free of otherpolymorph forms is different. In preparing polymorph form A, which isthe hemi-hydrate of the acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, it is best toutilize a solvent medium to dissolve a solid containing polymorph form Asuch as a mixture of polymorph forms A and B in an organic solvent whichcontains water. The preferred organic solvents that can be utilized inthis procedure include lower alkanol solvents such as methanol, butanol,ethanol or isopropanol as well as other solvents such as acetone,dichloromethane and tetrahydrofuran. In forming the purified polymorphform A substantially free of other polymorph forms, it is best toincorporate water in these solvents when preparing the medium forcrystallization. Once the solid, preferably a mixture of polymorph formsA and B, is dissolved in this medium, the solvent should be allowed toevaporate at room temperature over a long period of time while thesolution is exposed to the atmosphere. Room temperature can constituteany temperature from about 15° C. to 35° C. The evaporation can takeplace until all of the solvent medium is removed leaving the purifiedcrystals of polymorph form A. Preferably evaporation may be carried outnaturally such as by slow evaporation. Depending upon the amount of thesolution and its concentration, evaporation can take place over a periodfrom three to fifteen days or longer until the solvent is completedevaporated leaving a dry solid crystalline residue which is polymorphicform A substantially free of other polymorph forms.

Polymorph form B is the anhydrous form of the acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Polymorph form Bof the acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can be preparedfrom a solid containing polymorph form A such as a mixture of polymorphforms A and B by dissolving the polymorph form A or the mixture ofpolymorph forms A and B, preferably as the hydrochloride salt, utilizinganhydrous conditions. In accordance with a preferred embodiment of theinvention, this solid is in crystalline form and is re-crystallized byutilizing an anhydrous organic solvent. Any of the organic solventsmentioned hereinbefore can be utilized in their anhydrous form toproduce polymorph form B. As set forth above, it is important that there-crystallization take place under anhydrous conditions. In addition itis preferred that the removal of solvent to produce the crystalline formof polymorph B take place at elevated temperatures, i.e. from about 50°C. to 80° C., under anhydrous conditions. After crystallization ofpolymorph B from the solvent mixture, the solvent can be removed byfiltering or decanting to leave polymorph form B substantially free ofother polymorph forms. In preparing the crystallizing medium prior toremoval of the solvent, the formation of the crystallizing mediumcontaining the mixture of forms A and B for re-crystallization can takeplace at elevated temperatures, if desired, i.e. from 50° C. to 80° C.

Polymorph form C can be prepared from either polymorph form A orpolymorph form B or mixtures thereof. Polymorph form C is prepared byextensive heating of either polymorph form A or polymorph form B, ormixtures thereof, at temperatures of at least 50° C., preferably from60° C. to 80° C. Heating can be continued until polymorph form Csubstantially free of other polymorph forms is formed. This heating can,if desired, take place over long periods of time i.e. from 12 hours to 4days of longer, until the polymorph forms of the starting material areconverted to polymorph form C substantially free of other polymorphforms. The acid addition salt having the crystalline structure ofpolymorph form C substantially free of other polymorph forms is producedby extensive heating, usually not in the presence of a solvent, of theacid addition salts of poly-morph forms A and B. The preferred acidaddition salt in this preparation is the hydrochloride acid additionsalt form.

The techniques set forth above also allow for the preparation ofmixtures of the individual polymorph forms of the acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane containing specificamounts of each of the polymorphs. In particular, mixtures of polymorphform A and either polymorph form B or polymorph form C, polymorph form Band polymorph form C, and polymorph form A, polymorph form B andpolymorph form C can be readily prepared with the desired amounts ofeach of the polymorphs. By way of example and not of limitation, amixture of polymorph form A and polymorph form B containing the desiredamount of each polymorph can be prepared by subjecting polymorph form Asubstantially free of other polymorph forms and prepared as describedabove to the procedure for preparation of polymorph form B describedabove for the period of time needed to produce the desired amount ofpolymorph form B. By way of further example, a mixture of polymorph formA and polymorph form C containing the desired amount of each polymorphcan be prepared by subjecting polymorph form A substantially free ofother polymorph forms and prepared as described above to the procedurefor preparation of polymorph form C described above for the period oftime needed to produce the desired amount of polymorph form C. By way ofadditional example, a mixture of polymorph form B and polymorph form Ccontaining the desired amount of each polymorph can be prepared bysubjecting polymorph form B substantially free of other polymorph formsand prepared as described above to the procedure for preparation ofpolymorph form C described above for the period of time needed toproduce the desired amount of polymorph form C. By way of furtherexample, mixtures of polymorph form A and either polymorph form B orpolymorph form C, polymorph form B and polymorph form C, and polymorphform A, polymorph form B and polymorph for in C containing the desiredamount of each polymorph can be prepared by combining the desiredpolymorphs substantially free of other polymorph forms and prepared asdescribed above so that the desired mixture is obtained.

Using the techniques set forth above, mixtures containing specificpercentages of the individual polymorphic forms of the acid additionsalt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can beobtained. For example, mixtures containing from about 10% to about10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99% orgreater (by weight) of polymorph form A, with the remainder of themixture being either or both polymorph form B and polymorph form C, canbe prepared. As another example, mixtures containing from about 10% toabout 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99% orgreater (by weight) of polymorph form B, with the remainder of themixture being either or both polymorph form A and polymorph form C, canbe prepared. As a further example, mixtures containing from about 10% toabout 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99% orgreater (by weight) of polymorph form C, with the remainder of themixture being either or both polymorph form A and polymorph form B, canbe prepared.

Additionally, many pharmacologically active organic compounds regularlycrystallize incorporating second, foreign molecules, especially solventmolecules, into the crystal structure of the principal pharmacologicallyactive compound to for in pseudopolymorphs. When the second molecule isa solvent molecule, the pseudopolymorphs can also be referred to assolvates. All of these additional forms of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are likewisecontemplated by the present invention.

The polymorph forms A, B and C of the present invention can be preparedas acid addition salts formed from an acid and the basic nitrogen groupof (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Suitable acidaddition salts are formed from acids, which form non-toxic salts,examples of which are hydrochloride, hydrobromide, hydroiodide,sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate.Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts. The pharmaceutically acceptable saltsinclude, but are not limited to, metal salts such as sodium salt,potassium salt, cesium salt and the like; alkaline earth metals such ascalcium salt, magnesium salt and the like; organic amine salts such astriethylamine salt, pyridine salt, picoline salt, ethanolamine salt,triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; organic acid salts suchas acetate, citrate, lactate, succinate, tartrate, maleate, fumarate,mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formateand the like; sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate, tartrate, gluconate and the like. Thehydrochloride salt formed with hydrochloric acid is an exemplary usefulsalt.

The above individual polymorph forms and mixtures of polymorph forms ofthe acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can be administeredto human patients in the same manner as the previously known forms of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Suitable routes ofadministration for the above individual polymorph forms and mixtures ofpolymorph forms of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane include, but arenot limited to, oral, buccal, nasal, pulmonary, aerosol, topical,transdermal, mucosal, injectable, slow release and controlled releasedelivery, although various other known delivery routes, devices andmethods can likewise be employed. Useful parenteral delivery methodsinclude, but are not limited to, intravenous, intramuscular,intraperitoneal, intraspinal, intrathecal, intracerebroventricular,intraarterial, and subcutaneous injection.

Suitable effective unit dosage amounts for the above individualpolymorphic forms and mixtures of polymorphic forms of an acid additionsalt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane formammalian subjects may range from about 1 to 1200 mg, 50 to 1000 mg, 75to 900 mg, 100 to 800 mg, or 150 to 600 mg. In certain embodiments, theeffective unit dosage will be selected within narrower ranges of, forexample, about 10 to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 150 mg,150 to 250 mg or 250 to 500 mg. These and other effective unit dosageamounts may be administered in a single dose, or in the form of multipledaily, weekly or monthly doses, for example in a dosing regimencomprising from about 1 to 5, or 2-3, doses administered per day, perweek, or per month. In exemplary embodiments, dosages of about 10 to 25mg, 30 to 50 mg, 75 to 100 mg, 100 to 200 (anticipated dosage strength)mg, or 250 to 500 mg, are administered one, two, three, or four timesper day. In more detailed embodiments, dosages of about 50-75 mg,100-150 mg, 150-200 mg, 250-400 mg, or 400-600 mg are administered once,twice daily or three times daily. In alternate embodiments, dosages arecalculated based on body weight, and may be administered, for example,in amounts from about 0.5 mg/kg to about 30 mg/kg per day, 1 mg/kg toabout 15 mg/kg per day, 1 mg/kg to about 10 mg/kg per day, 2 mg/kg toabout 20 mg/kg per day, 2 mg/kg to about 10 mg/kg per day or 3 mg/kg toabout 15 mg/kg per day.

Using the routes and methods of administration and dosage amountsdescribed hereinabove and the dosage forms described hereinbelow, theindividual polymorph forms and mixtures of polymorph forms of thepresent invention can be used for the prevention and treatment ofvarious diseases and conditions in humans. By way of example and not oflimitation, in the case of depression, this is accomplished byadministering to a patient in need of said treatment who is sufferingfrom depression a composition containing one of the above polymorphforms substantially free of other polymorph forms or mixtures ofpolymorphs and an inert carrier or diluent, said composition beingadministered in an effective amount to prevent or treat said depression.In accordance with this invention,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, either as apolymorph form substantially free of other polymorph forms or as amixture of polymorph forms, is administered in an effective amount toprevent or treat depression. Any effective amount of such polymorph formsubstantially free of other polymorph forms or mixtures of polymorphforms needed to prevent or treat depression can be utilized in thiscomposition. In general, in the case oral dosage forms, dosages of fromabout 0.5 mg/kg to about 5.0 mg/kg of body weight per day are used.However the amount of such polymorph form substantially free of otherpolymorph forms or mixtures of polymorph forms in the oral unit dose tobe administered will depend to a large extent on the condition ofdepression and the weight of the patient and of course be subject to thephysician's judgment. In accordance with this invention, the oral unitdosage form containing the given polymorph form substantially free ofother polymorph forms or mixtures of polymorph forms can be preferablyadministered at a dosage of from about 30 mg to 300 mg per day, morepreferably from about 50 mg to about 200 mg per day, administered onceor twice during the day or as needed.

The present invention includes pharmaceutical dosage forms for the aboveindividual polymorph forms and mixtures of polymorph forms of an acidaddition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.Such pharmaceutical dosage forms may include one or more excipients oradditives, including, without limitation, binders, fillers, lubricants,emulsifiers, suspending agents, sweeteners, flavorings, preservatives,buffers, wetting agents, disintegrants, effervescent agents and otherconventional excipients and additives. The compositions of the presentinvention can thus include any one or a combination of the following: apharmaceutically acceptable carrier or excipient; other medicinalagent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives;diluents; and various other pharmaceutical additives and agents known tothose skilled in the art. These additional formulation additives andagents will often be biologically inactive and can be administered topatients without causing deleterious side effects or interactions withthe active agent.

As previously noted, polymorph form A is a thermodynamically stablepolymorph of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Therefore, it ispreferred that polymorph form A be used in pharmaceutical dosage formswithout the presence of other geometrical, optical and polymorphicisomers of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.However, polymorph forms B and C can also be included in pharmaceuticalproduct formulations with less positive results concerning formulationand stability.

If desired, the individual polymorph forms or mixtures of polymorphforms of the present invention can be administered in a controlledrelease form by use of a slow release carrier, such as a hydrophilic,slow release polymer. Exemplary controlled release agents in thiscontext include, but are not limited to, hydroxypropyl methyl cellulose,having a viscosity in the range of about 100 cps to about 100,000 cps.

The individual polymorph forms or mixtures of polymorph forms of thepresent invention can be formulated and administered in oral dosageform, optionally in combination with a carrier or other additive(s).Suitable carriers common to pharmaceutical formulation technologyinclude, but are not limited to, microcrystalline cellulose, lactose,sucrose, fructose, glucose, dextrose, other sugars, di-basic calciumphosphate, calcium sulfate, cellulose, methylcellulose, cellulosederivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol,other sugar alcohols, dry starch, dextrin, maltodextrin, otherpolysaccharides, or mixtures thereof.

Exemplary oral unit dosage forms for use in the present inventioninclude tablets, capsules, powders, solutions, syrups, suspensions andlozenges, which may be prepared by any conventional method of preparingpharmaceutical oral unit dosage forms. Oral unit dosage fowls, such astablets, may contain one or more of the conventional, pharmaceuticallyacceptable additional formulation ingredients, including but not limitedto, release modifying agents, glidants, compression aides,disintegrants, effervescent agents, lubricants, binders, diluents,flavors, flavor enhancers, sweeteners and preservatives. Theseingredients are selected from a wide variety of excipients known in thepharmaceutical formulation art. Depending on the desired properties ofthe oral unit dosage form, any number of ingredients may be selectedalone or in combination for their known use in preparing such dosageforms as tablets.

Suitable lubricants include stearic acid, magnesium stearate, talc,calcium stearate, hydrogenated vegetable oils, sodium benzoate, leucinecarbowax, magnesium lauryl sulfate, colloidal silicon dioxide andglyceryl monostearate. Suitable glidants include colloidal silica, fumedsilicon dioxide, silica, talc, fumed silica, gypsum and glycerylmonostearate. Substances which may be used for coating includehydroxypropyl cellulose, titanium oxide, talc, sweeteners and colorants.The aforementioned effervescent agents and disintegrants are useful inthe formulation of rapidly disintegrating tablets known to those skilledin the art. These typically disintegrate in the mouth in less than oneminute, and often in less than thirty seconds. By effervescent agent ismeant a couple, typically an organic acid and a carbonate orbicarbonate.

The following examples illustrate certain embodiments of the presentinvention, and are not to be construed as limiting the presentdisclosure.

EXAMPLES Example 1

This example is directed to preparing the hydrochloride salt of(+)-1-(3,4 dichlorophenyl)-3-azabicyclo[3.1.0]hexane from the free baseof (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and todemonstrate that this method produced a mixture of polymorph form A andpolymorph form B.

Approximately 250 mg of the free base of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane was dissolved in400 mL 95:5 (v/v) hexane/isopropanol (with 0.05% diethylamine). Thesolution was evaporated under a nitrogen stream on a stir plate set atapproximately 70° C., concentrating the sample to a clear gel. This gelwas dissolved in 50 mL ethyl acetate and dried under a nitrogen stream,yielding a thin, clear to off-white (tint of yellow), milky residue.This residue was dissolved in 7 mL diethyl ether, and 7 mL HCl saturateddiethyl ether was added; chunks of white solid were precipitatedimmediately. This solid was recovered through vacuum filtration andwashed with 19 mL diethyl ether. The filtered solid appeared dry. The(+)-1-(3,4-dichlorophoyl)-3-azabicyclo[3.1.0]hexane hydrochloride saltwas recovered (162.5 mg), resulting in a yield of 55.7%.

XRPD analysis and Raman spectroscopy performed as described aboveindicated that both the starting material (free base) and end product(hydrochloride salt) constituted a mixture of polymorph form A andpolymorph form B. Both the starting material and end product wereobserved to contain approximately 50% (by weight) of each polymorph.There was only a minor difference in the % of these polymorphs in thestarting material and in the final product.

Example 2 Stability Studies on the End Product of Example 1

Duplicate samples of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane produced in Example1 and containing a 50% (by weight) mixture of polymorph form A andpolymorph form B were placed on informal stability to test storage indesiccators placed at ambient temperature and at 50° C. in aprogrammable heating bloc. The samples were examined after 1 week andwhile both samples contained mixtures of polymorph form A and polymorphform B, the ratios observed showed some conversion of forms. The mixturesubjected to ambient temperature was observed to contain 40% (by weigh)of polymorph form A and 60% (by weight) of polymorph form B (asdetermined by XPRD analysis?). This result was confirmed by Ramanspectroscopy. Subsequent XRPD analysis of the sample stored in a 50° C.programmable heating block showed about 50% (by weight) of polymorphform A and 50% (by weight) of polymorph form C after 17 days of storage.

Example 3 Method of Manufacture of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride Step1: Synthesis of α-bromo-3,4-dichlorophenylacetic acid methyl ester

100 kg 3,4-dichlorophenylacetonitrile was added in portions over 1.25hours to a mixture of 12 kg water and 140 kg 98% sulfuric acid. Exothermwas allowed to 65° C. maximum, and the reaction mix was maintained at60-65° C. for 30 minutes. After cooling to 50° C., 80 kg methanol wasslowly added over 25-30 minutes. The mixture was warmed to 92-98° C.,and maintained at this temperature for an additional three hours. Aftercooling to 35° C., the reaction mixture was quenched into an agitatedmixture (precooled to 0-5° C.) of 150 L ethylene dichloride and 250 Lwater. The reactor and lines were washed with water into the quench mix,which was agitated 5 minutes and allowed to stratify. The lower organicphase was separated, and the aqueous phase washed with 2×150 L ethylenedichloride. The combined organic phases were washed with 100 L water andthen with aqueous sodium carbonate (3 kg sodium carbonate in 100 Lwater). The solution of crude ester was azeotropically “dried” in vacuoat 60-620 C, resulting in the collection of 100 L ethylene dichloride. Atheoretical yield was assumed without isolation and the solution wasused “as is” in the following bromination reaction.

A mixture of the solution (line-filtered) of crude methyl3,4-dichlorophenylacetate (from above) and 88 kg1,3-dibromo-1,3-dlmethylhydantoin (DBDMH) was warmed to 80° C., and asolution of 2.5 kg VAZO 52 in 15 L ethylene dichloride was added portionwise over a 5 hour period, maintaining 85-90° C. (under reflux). Anadditional 8.8 kg DBDMH was then added, and a solution of 0.5 kg VAZO 52in 4 L ethylene dichloride was added portion wise over a 2.5 hourperiod, maintaining 85-90° C. (under reflux). Heating was thendiscontinued, and 350 L water was added with agitation. The mixture wasallowed to stratify, the lower organic phase was separated and theaqueous phase was washed with 50 L ethylene dichloride. The combinedorganic phases were washed with aqueous thiosulfate (5.0 kg sodiumthiosulfate in 150 L water), aqueous sodium carbonate (2.5 kg sodiumcarbonate in 150 L water), and dilute hydrochloric acid (5.4 L 32% HClin 100 L water). The organic phase was line-filtered and distilled invacuo to “dryness” (full vacuum to 83° C.). Residual ethylene dichloridewas chased with 20 kg toluene (full vacuum at 83° C.). The crudeα-bromo-3,4-dichlorophenylacetic acid methyl ester was taken up in 82 kgtoluene, cooled to 40° C., and discharged to steel drums. The productwas not isolated, and was used “as is” in Step 2. A theoretical yieldwas assumed for calculation purposes.

Step 2: Synthesis of 1-(3,4-dlchlorophenyl-1,2-cyclopropane-dicarboxylicacid dimethyl ester

The crude α-bromo-3,4-dichlorophenylacetic acid methyl ester from Step 1was mixed well with 55.6 kg methyl acrylate, and then the mixture wasadded to a precooled (−2° C.) mixture of 54.4 kg potassium methoxide in500 L toluene (argon blanket) over 5.5 hours with good agitation andmaintained at <+10° C. After standing overnight (5 psig argon) withbrine cooling (−5° C.), the cold reaction mixture was quenched into amix of 250 L water and 30 kg 32% hydrochloric acid with good agitation.200 L water and 2.5 kg potassium carbonate were added to the mixturewith good agitation for an additional 30 minutes. After stratification,the lower aqueous phase was separated, and 150 L water and 1.0 kgpotassium carbonate were added to the organic phase. The mixture wasagitated 5 minutes and stratified. The lower aqueous phase was separatedand discarded, as well as the interfacial emulsion, and the organicphase was washed with 100 L water containing 1 L 32% hydrochloric acid.After stratification and separation of the lower aqueous phase, theorganic phase was line-filtered and distilled in vacuo to “dryness”(full vacuum at 65° C.). To the hot residue was added 70 kg methanolwith agitation. The mix was cooled (seeding at +10° C.) to −5° C. andmaintained at this temperature overnight. The cold thick suspension wassuction-filtered (Nutsche), and the cake of1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid dimethyl esterwas suction dried, washed with 2×20 L hexane, suction dried for 30minutes and air-dried on paper (racks) for 2 days at ambient conditions.

To the methanolic liquors was added 50 kg caustic soda flake portionwise over 8 hours with good agitation. After gassing and the slowexotherm (60° C. maximum) ceased, the heavy suspension was held at 50°C. for 1 hour. 100 L isopropanol was slowly added over 10 minutes, andthen the mixture was agitated slowly overnight at ambient conditions.The solids were suction-filtered (Nutsche) and reslurried with 80 Lmethanol. The resulting1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid disodium saltwas suctioned-filtered (Nutsche), washed with methanol (40 L), suctiondried for 1 hour and air-dried on paper (racks).

Step 3: Synthesis of1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid

A suspension of 42.0 kg1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid disodium salt(from Step 2) and 120 L deionized water was warmed to 30-35° C., and thesolution was line-filtered and neutralized with 30 kg 32% hydrochloricacid to precipitate the free dicarboxylic acid. 120 kg ethyl acetate wasadded, and the mix warmed to 40-50° C. to effect solution. The loweraqueous phase was separated and washed with 20 kg ethyl acetate. Thecombined organic extracts were washed with saturated sodium chloride (3kg in 30 L water) and then distilled in vacuo to “dryness” (full vacuumto 70° C.). 60 kg ethylene dichloride was added to the warm residue, andthe solution cooled with slow agitation at −5° C. overnight. Residualethyl acetate was distilled (full vacuum to 43° C.) to yield a thicksuspension, which was then cooled with full vacuum to −5° C. over a 2.5hour period and then suction-filtered (Nutsche). The1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid cake waswashed with cold ethylene dichloride (2×5 L), followed by ambientethylene dichloride (4×5 L). The dicarboxylic acid product was suctiondried for 15 minutes and air-dried on paper (racks).

A mixture of 31.0 kg1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid dimethyl ester(from Step 2), 40 L water, 35 kg methanol and 18.0 kg 50% caustic sodawas warmed to 70-75° C. (under reflux) and maintained at 70-75° C. for1.5 hours. 10 L water was then added, and the mixture was kept at 75-77°C. for an additional 2 hours. Methanol was slowly distilled off in vacuoto 70° C. to give a heavy suspension, which was then mixed with 80 Lwater to effect solution. The free dicarboxylic acid was precipitatedwith 31 kg of 32% hydrochloric acid and extracted with 100 kg ethylacetate. The lower aqueous phase was separated and washed with 20 kgethyl acetate. The combined organic phases were washed with 50 L water,and then saturated aqueous sodium chloride. Distillation in vacuo to 80°C. with full vacuum yielded a concentrate of1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid, which wasused “as is” for the next step, cyclization to the imide. A quantitativeyield from the diester was assumed for calculation purposes.

Step 4: Synthesis and Recrystallization of1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

The slurry of 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid(from Step 3) was added to 45.6 kg warm (68° C.) formamide, and residualethyl acetate was distilled with full vacuum at 68-73° C. An additional14.4 kg formamide was added to the mixture, followed by 11.2 kg of thedicarboxylic acid (derived from the disodium salt, Step 3). An argonblanket on the mixture was maintained for the following operation. Themixture was agitated 15 minutes at 73-75° C. to effect a completesolution, and then heated over a 1 hour period to 140-145° C. andmaintained at this temperature for an additional 2.25 hours. Heating wasdiscontinued, and the mixture was cooled to 70° C. and 10 L watercontaining 20 ml 32% HCl was slowly added over 30 minutes. The mixturewas seeded and crystallization commenced. An additional 20 L water wasslowly added to the heavy suspension over a 2 hour period. Afterstanding overnight at ambient conditions, the mixture was agitated for1.25 hours at ambient temperature and then suction-filtered (Nutsche).The cake of crude1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane-2,4-dione was washedwith water (3×20 L), suction dried for 30 minutes and air-dried on paper(racks) for 2 days under ambient conditions.

A mixture of 37 kg crude, damp1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane-2,4-dione (from Step4, above) and 120 L toluene was warmed to 75-80° C. to effect solution.After stratification and separation of the residual water (3.3 kg), 1 kgDarco G-60 activated carbon (American Norit Co.) (suspended in 5 Ltoluene) was added. The mixture was agitated at 80° C. for 30 minutesand then pressure filtered through a preheated Sparkler (precoated withfilteraid), polishing with a 10 μm in-line filter. The clear lightyellow solution was concentrated in vacuo at 75-80° C. to 100 L finalvolume and slowly cooled, with seeding at 70° C. The heavy crystallinesuspension was cooled to −5° C., held 30 minutes at this temperature andsuction-filtered (Nutsche). The cake of purified1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane-2,4-dione was washedwith 2×10 L cold (−10° C.) toluene, and then 2×20 L hexane. Aftersuction drying for 30 minutes, the 2,4-dione product was dried in vacuo(≦62° C.).

Step 5: Synthesis and Purification of(±)-1-(3,4-Dichloroohenyl)-3-azabicyclo [3.1.0]hexane hydrochloride

BH3-THF complex is charged into a 2 L addition funnel (9×2 L, then 1×1.5L) and drained into a 50 L flask.

1000 g of (±)-1-(3,4dichlorophenyl)-3-azabicyclo[3.1.0]-hexane-2,4-dione is dissolved in 2 Lof THF and added to the BH3-THF dropwise over a period of 2 hours. Thereaction mixture is heated to reflux and held at this temperatureovernight. The mixture is then cooled to <10° C., adjusted to pH 2 withthe addition of 1200 mL of 6N HCl dropwise at <20° C., and stirred for aminimum of 1 hour.

The reaction mixture is then transferred to a 10 L Buchi flask,concentrated to a milky white paste, and transferred again to a 5-galloncontainer. The mixture is diluted with 4 L of cold water and adjusted topH 10 with 2000 mL of a 25% sodium hydroxide solution. A temperature of<20° C. is maintained. Following this, 4.5 L of ethyl acetate is addedand the mixture is stirred for 15 minutes. The solution is then filteredthrough a 10 inch funnel with a filter cloth and washed with ethylacetate (2×250 mL).

The filtrate is then transferred into a 40 L separatory funnel and thephases are allowed to separate. Each phase is then drained into separate5-gallon containers. The aqueous layer is returned to the 40 Lseparatory funnel and extracted with ethyl acetate (2×2 L). The organicphases are combined. The aqueous layer is discarded.

250 g of magnesium sulfate and 250 g of charcoal are added to thecombined organics and the mixture is stirred well. The solution is thenfiltered through an 18.5 cm funnel using a filter pad and washed withethyl acetate (2×250 mL). The filtrate is then transferred to a 10 LBuchi flask and concentrated to dryness. The resulting yellowish oil isdiluted with ethyl acetate (2.25 mL/g).

HCl gas is bubbled through a 12 L flask containing 10 L of ethyl acetateto make an approximately 2.3 M solution of HCI/ethyL acetate. ThisHCI-ethyl acetate solution is added to the oil dropwise at a rate thatmaintains a temperature of <20° C. using an ice/water bath. The solutionis then stirred at <10° C. for a minimum of 2 hours in the ice/waterbath. The material is chilled in a cold room overnight.

The resulting solids are then filtered through a 10 inch funnelutilizing a filter cloth and washed with ethyl acetate (2×200 mL) andethyl ether (3×500 mL). The product, crude(±)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]-hexane hydrochloride, isthen transferred to Pyrex drying trays and dried for 4 hours.

1900 g of crude (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride from above, and 15.2 L of isopropyl alcohol are charged toa 22 L flask. The mixture is heated to dissolve all material.

The material is then filtered through a 18.5 cm funnel utilizing afilter pad and transferred to a 22 L flask. The solution is then stirredat room temperature for 1 hour. The solution is then chilled to 4° C.with an ice/water bath and stirred for 3.75 hours. The product is thenplaced in a cold room overnight.

The solids are then filtered through a 13 inch filter using a filtercloth and washed with ethyl ether (3×633 mL). The product is then airdried for 2 hours.

The product, pure (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride, is transferred to clean Pyrex drying trays and dried toconstant weight.

Step 6: Resolution of(±)-1-(S3,4-dichlorophenyl)-3-azabicyclor[3.1.0]hexane hydrochlorideinto (+)-1-(3,4-dichlorophenyl)-3-azablcyclo[3.1.0]hexane hydrochloride

In a 50 gallon reactor containing 60 L of 15% NaOH, 13.6 kg of pure(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (fromStep 5, above) is added while keeping the temperature constant atapproximately 20° C. Once the addition of(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride iscomplete, the reaction mixture is allowed to stir at room temperaturefor a minimum of 8 hours.

40 L of ethyl acetate is added to the reactor and the two phase mixtureis stirred until a clear solution is obtained (approximately 2 hours).The phases are allowed to separate and the organic layer is transferredto another 50 gallon reactor. The remaining aqueous layer is extractedwith ethyl acetate (6×6 L). All organic phases are combined into the50-gallon reactor. The organic phase is dried and decolorized by theaddition of 4000 g magnesium sulfate and 250 g of charcoal. The mixtureis then filtered through an in-line filter. The filtrate is transferredvia in-line filter to a 50-gallon reactor.

In a separate 50-gallon reactor, 23,230 g of L-(−)-dibenzoyl tartaricacid is dissolved with stirring (approximately 30 minutes) in 71 L ofmethanol. The dissolution is assisted with heating if necessary.

The L-(−)-dibenzoyl tartaric acid solution in methanol is added viaaddition funnel to the reactor containing the filtrate, over a period ofapproximately 1 hour, maintaining the temperature at 15-25° C. After theaddition is complete the mixture is stirred for approximately 16 hoursat 15-25° C. Following stirring, 50 L of methanol is added to themixture and it is stirred again for 30 additional minutes. The resultingsolids are filtered onto a plate filter. The solids are then washed withmethanol (3×5 L) and pressed dry. The crude solids are weighed andtransferred to a 50-gallon reactor to which 80 L of methanol is added.The mixture is heated to reflux and stirred at reflux for approximately30 minutes. The mixture is then cooled to 15-20° C. and stirred at thistemperature for approximately 2 hours. The resulting solids are filteredonto a plate filter using a polypropylene filter cloth. The cake iswashed with methanol (3×5 L) and pressed dry. The solids are transferredto a tarred 5-gallon container and weighed (yield ˜20 kg).

The solids are then added (over a period of approximately 1 hour) to a50 gallon reactor vessel containing 60 L of 15% NaOH while maintainingthe temperature at approximately 20° C. Once the addition of the solidsis complete the reaction mixture is stirred for approximately 19 hours.

40 L of ethyl acetate is charged to the reactor, while maintaining thetemperature at ≦3.5° C. and the two phase mixture is stirred until aclear solution is obtained (approximately 2 hours). The phases areallowed to separate and the organic layer is transferred to another 50gallon reactor. The remaining aqueous layer is extracted with ethylacetate (6×6 L). All organic phases are combined into the 50-gallonreactor. 0.5000 g of magnesium sulfate is then added to the organicphase. The mixture is then filtered through an in-line filter. Thefiltrate is transferred via in-line filter to a 50-gallon reactor. Thefiltrate is concentrated to a total volume of 20-30 L.

In a 22 L three neck round bottom flask, HCl gas is bubbled through 12 Lof ethyl acetate to make an approximately 2.3 M solution of HCI/ethylacetate. After titration assay, the solution is adjusted to exactly 2.3M by adding either ethyl acetate or HCl gas.

8.2 L of the 2.3 M solution of HCI/ethyl acetate is added (over a periodof approx. 1.5 hours) to the filtrate (above), maintaining thetemperature at ≦20° C. and ensuring that a pH of 2 is obtained. Once theaddition is complete, the mixture is stirred at 0 to −5° C. for a periodof 16 hours.

The resulting solids, crude(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride, arefiltered onto a plate filter using a polypropylene filter cloth. Thesolids are then washed with ethyl acetate (2×2 L), acetone (2×2 L) andethyl ether (2×2 L) and dried under vacuum. The material is transferredto a tarred 5-gallon polyethylene container and weighed.

Step 6a: Recrystallization of(−)-1-(3,4-dichloroPhenyl)-3-azabicyclor3.1.01hexane hydrochloride fromisopropanol

The solids (from Step 6, above) are transferred to a 50-gallon reactorand isopropanol is added (8-10 mL/g of solid). The mixture is heated toreflux. The solution is filtered through an in-line filter into another50 gallon reactor. The solution is cooled to 0 to −5° C. and maintainedat this temperature with stirring for approximately 2 hours. Theresulting solids are filtered onto a plate filter using a polypropylenefilter cloth. The solids are then washed with ethyl acetate (2×2 L),acetone (2×2 L) and ethyl ether (2×2 L). The solids are dried undervacuum.

The product, (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride, is transferred into clean, tarred drying tray(s). Thetray(s) are placed in a clean, vacuum drying oven. The product is driedat 50° C. to constant weight. The material is dried for a minimum of 12hours at <10 mm Hg. This product was a mixture of polymorph form A andpolymorph form B, with each polymorph present in the mixture in anamount of about 50% by weight. This product was used as the startingmaterial for Examples 4 through 8 below.

Example 4

The 50% by weight mixture of polymorph form A and polymorph form B ofthe hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (54 mg) wasdissolved in 12 ml of acetonitrile and water. Approximately half of thisstock solution was then filtered through a 0.2:m nylon syringe filterinto a clean vial. The vial was covered with aluminum foil puncturedwith a pinhole and left in a fume hood under ambient conditions for slowevaporation. After allowing the solvent in the vial to evaporate, whichoccurred in about four days, a crystal residue was obtained which wasthe pure polymorph form A form of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as demonstrated byRaman spectroscopy and XRPD analysis as described above

The same pure crystalline form was also obtained with other solventsprepared using the same method, such as acetone, 2-butanol,dichloromethane, ethanol, methanol, nitromethane, isopropanol andtetrahydrofuran. These solvents also contained water.

Example 5

68 mg of the 50% by weight mixture of polymorph form A and polymorphform B of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane was dissolved in3.4 ml of ethyl ether:ethanol (1:1 ratio) solvent mixture. The resultedsolution was filtered through a 0.2:m nylon syringe filter into a cleanvial. Solid samples were collected by rotary evaporation of the solventsunder vacuum. The solids were than dried under vacuum at ambienttemperature to produce pure polymorph form B crystals of thehydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as demonstrated byRaman spectroscopy and XRPD analysis as described above.

Example 6

51 mg of the 50% by weight mixture of polymorph form A and polymorphform B of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane was weighed into avial. The vial was covered with aluminum foil perforated with pinholesand placed in an oven at 80° C. for 4 days to produce the pure polymorphC crystals of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as demonstrated byRaman spectroscopy and XRPD analysis as described above.

Example 7 Preparation of Polymorph Form B

40 mg samples of the 50% by weight mixture of polymorph form A andpolymorph foam B of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane were mixed with 0.5mL of anhydrous acetonitrile to produce a concentration of about 80-100mg/mL and the resulting samples were stirred at various temperaturesbetween 50° C. and 80° C. for various periods of time (some for 4 daysand 6 days at about 50° C. and some for 1 day at about 80° C.). Theresulting samples were each mixtures of a clear liquid and some solid.The clear liquid was decanted off, and the remaining solid was vacuumdried at ambient temperature for 1 hour to 2 days (50° C. sample), or 6days (80° C. sample) to afford pure crystalline polymorph form B. Allsamples produced the pure polymorph form B crystals of the hydrochloridesalt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane asdemonstrated by Raman spectroscopy and XRPD analysis as described above.

Example 8 Preparation of Polymorph Form A

20 mg samples of the 50% by weight mixture of polymorph form A andpolymorph form B of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane were dissolved in0.5 ml of aqueous ethanol. Other samples were prepared by dissolving 20mg of this mixture in 0.5 mL of water. Both solutions were filteredthrough a 0.2 micron nylon filter. Both filtered solutions were thenallowed to evaporate under ambient conditions, some samples partiallycovered and other samples completely uncovered. After 6 days, both theuncovered and partially covered ethanol solution samples evaporated.After 7 days, the uncovered water solutions evaporated. After 15 days,the partially covered water solutions evaporated. For each sample, afterthe solvent (either aqueous ethanol or water) evaporated completely, 20mg of dry solid residue was left. The solid in all samples thus producedwas the pure polymorph form A crystals of the hydrochloride salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as demonstrated byRaman spectroscopy and XRPD analysis as described above.

1. A polymorph of an acid addition salt of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof.
 2. The acid addition salt of claim 1 wherein said salt is ahydrochloride salt.
 3. The polymorph form A of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof.
 4. The polymorph form A of claim 3 wherein said acid additionsalt is a hydrochloride salt.
 5. The polymorph form A of claim 4 whereinthe X-ray powder diffraction pattern of said polymorph, as measured atcrystal sizes of from about 10 to 40 microns, is characterized by peaksat one or more of and at about the following °2θ (degree) values: 17.14;19.62; 21.96; 24.52; and 26.74.
 6. The polymorph form A of claim 4wherein the X-ray powder diffraction pattern of said polymorph, asmeasured at crystal sizes of from about 10 to 40 microns, ischaracterized by peaks at all of and at about the following °2θ (degree)values: 17.14; 19.62; 21.96; 24.52; and 26.74.
 7. The polymorph form Aof claim 4 wherein Raman spectrum of said polymorph is characterized bypeaks at one or more of and at about the following wavenumbers (cm⁻¹):762; 836; 921; 959; 1393; 1597; 2890; 2982; and
 3064. 8. The polymorphform A of claim 4 wherein the Raman spectrum of said polymorph ischaracterized by peaks at all of and at about the following wavenumbers(cm⁻¹): 762; 836; 921; 959; 1393; 1597; 2890; 2982; and
 3064. 9. Thepolymorph form B of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof.
 10. The polymorph form B of claim 9 wherein said acid additionsalt is a hydrochloride salt.
 11. The polymorph form B of claim 10wherein the X-ray powder diffraction pattern of said polymorph, asmeasured at crystal sizes of from about 10 to 40 microns, ischaracterized by peaks at one or more of and at about the following °2θ(degree) values: 15.58; 17.52; 21.35; 23.04; 25.43; and 30.72.
 12. Thepolymorph form B of claim 10 wherein the X-ray powder diffractionpattern of said polymorph, as measured at crystal sizes of from about 10to 40 microns, is characterized by peaks at all of and at about thefollowing °2θ (degree) values: 15.58; 17.52; 21.35; 23.04; 25.43; and30.72.
 13. The polymorph form B of claim 10 wherein the Raman spectrumof said polymorph is characterized by peaks at one or more of and atabout the following wavenumbers (cm⁻¹): 1245; 1380; 2963; 2993; 3027;and
 3066. 14. The polymorph form B of claim 10 wherein the Ramanspectrum of said polymorph is characterized by peaks at all of and atabout the following wavenumbers (cm⁻¹): 1245; 1380; 2963; 2993; 3027;and
 3066. 15. The polymorph form C of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof.
 16. The polymorph form C of claim 15 wherein said acid additionsalt is a hydrochloride salt.
 17. The polymorph form C of claim 16wherein the X-ray powder diffraction pattern of said polymorph, asmeasured at crystal sizes of from about 10 to 40 microns, ischaracterized by peaks at one or more of and at about the following °2θ(degree) values: 13.34; 17.64; 20.07; 21.32; 22.97; 24.86; 26.32; and27.90.
 18. The polymorph form C of claim 16 wherein the X-ray powderdiffraction pattern of said polymorph, as measured at crystal sizes offrom about 10 to 40 microns, is characterized by peaks at all of and atabout the following °2θ (degree) values: 13.34; 17.64; 20.07; 21.32;22.97; 24.86; 26.32; and 27.90.
 19. The polymorph form C of claim 16wherein the Raman spectrum of said polymorph is characterized by peaksat one or more of and at about the following wavenumbers (cm⁻¹): 1059;1094; 1266; 1343; 1595; 2966; 2900; and
 3070. 20. The polymorph form Cof claim 16 wherein the Raman spectrum of said polymorph ischaracterized by peaks at all of and at about the following wavenumbers(cm⁻¹): 1059; 1094; 1266; 1343; 1595; 2966; 2900; and
 3070. 21. A methodof producing polymorph form A of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof comprising dissolving a solid containing one or more polymorphsof the acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] other than polymorph formA in a solvent medium containing water and allowing said solvent mediumto evaporate at a temperature of from about 15° C. to 35° C. whileexposed to the atmosphere to remove said solvent medium and produce saidpolymorph form A in crystalline form.
 22. The method of claim 21 whereinsaid solid is a mixture of polymorph forms A and B of an acid additionsalt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
 23. Themethod of claim 22 wherein said acid addition salt is a hydrochloridesalt.
 24. The method of claim 21 wherein said solvent medium contains alower alkanol.
 25. The method of claim 21 wherein the evaporation takesplace over a period of at least 4 hours until said solvent mediumevaporates.
 26. The polymorph form A in crystalline form produced inaccordance with the method of claim
 21. 27. A method of producingpolymorph form B of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof comprising dissolving a solid containing one or more polymorphsof the acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] other than polymorph formB in an anhydrous organic solvent and crystallizing from said solventunder anhydrous conditions at temperatures of from about 50° C. to 85°C. said polymorph form B in crystalline form.
 28. The method of claim 27wherein said acid addition salt is a hydrochloride salt.
 29. The methodof claim 27 wherein said solid is a mixture of polymorph forms A and Bof an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
 30. The polymorphform B in crystalline form produced in accordance with the method ofclaim
 27. 31. A method of producing polymorph form C of an acid additionsalt of (+)-1-(3,4-dichlorophenyl)-3azabicyclo[3.1.0]hexane incrystalline form substantially free of other geometric, optical andpolymorphic isomers thereof comprising heating a solid containing one ormore polymorphs of the acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane other thanpolymorph form C to a temperature of at least 50° C. until saidpolymorph form C in crystalline form is produced.
 32. The method ofclaim 31 wherein said acid addition salt is a hydrochloride salt. 33.The method of claim 31 wherein said solid is a mixture of polymorphforms A and B of an acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
 34. The method ofclaim 31 wherein said solid is a mixture of polymorph forms A, B and Cof an acid addition salt of(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
 35. The polymorphform C in crystalline form produced in accordance with the method ofclaim
 31. 36. A pharmaceutical composition in oral unit dosage formcomprising solid polymorph form A of a pharmaceutically acceptable acidaddition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane incrystalline form substantially free of other geometric, optical andpolymorphic isomers thereof and an inert pharmaceutically acceptablecarrier or diluent.
 37. The pharmaceutical composition of claim 36wherein said pharmaceutically acceptable acid addition salt is ahydrochloride salt.
 38. The oral unit dosage form of claim 37 whereinsaid polymorph form A in crystalline form is present in said oral unitdosage form in the amount of about 25 mg to about 300 mg.
 39. Thepharmaceutical composition of claim 38 wherein said oral unit dosageform is a tablet or capsule.
 40. A pharmaceutical composition in oralunit dosage form comprising solid polymorph form B of a pharmaceuticallyacceptable acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof and an inert pharmaceutically acceptable carrier or diluent. 41.The pharmaceutical composition of claim 40 wherein said pharmaceuticallyacceptable acid addition salt is a hydrochloride salt.
 42. The oral unitdosage form of claim 41 wherein said polymorph form B in crystallineform is present in said oral unit dosage form in the amount of about 50mg to about 200 mg.
 43. The pharmaceutical composition of claim 42wherein said oral dosage form is a tablet or capsule.
 44. Apharmaceutical composition in oral unit dosage form comprising solidpolymorph form C of a pharmaceutically acceptable acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof and an inert pharmaceutically acceptable carrier or diluent. 45.The pharmaceutical composition of claim 44 wherein said pharmaceuticallyacceptable acid addition salt is a hydrochloride salt.
 46. Thepharmaceutical composition of claim 45 wherein said oral dosage form isa tablet or capsule.
 47. A method for the prevention or treatment ofdepression in a patient in need of said treatment comprisingadministering to said patient a composition containing polymorph form Aof a pharmaceutically acceptable acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline formsubstantially free of other geometric, optical and polymorphic isomersthereof and an inert carrier or diluent, said composition beingadministered in an effective amount to prevent or treat said depression.48. The method of claim 47 wherein said pharmaceutically acceptable saltis the hydrochloride salt.
 49. The method of claim 48 wherein saidpolymorph form A is administered to the patient at an oral dose of fromabout 0.5 mg/kg to about 5.0 mg/kg of body weight per day.
 50. A methodfor the prevention or treatment of depression in a patient in need ofsaid treatment comprising administering to said patient a compositioncontaining polymorph form B of a pharmaceutically acceptable acidaddition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane incrystalline form substantially free of other geometric, optical andpolymorphic isomers thereof and an inert carrier or diluent, saidcomposition being administered in an effective amount to prevent ortreat said depression.
 51. The method of claim 50 wherein saidpharmaceutically acceptable salt is the hydrochloride salt.
 52. Themethod of claim 51 wherein said polymorph form B is administered to thepatient at an oral dose of from about 0.5 mg/kg to about 5.0 mg/kg ofbody weight per day.
 53. A method for the prevention or treatment ofdepression in a patient in need of said treatment comprisingadministering to said patient a composition containing polymorph form Cof a pharmaceutically acceptable acid addition salt of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystallinefolio substantially free of other geometric, optical and polymorphicisomers thereof and an inert carrier or diluent, said composition beingadministered in an effective amount to prevent or treat said depression.54. The method of claim 53 wherein said pharmaceutically acceptable saltis the hydrochloride salt.
 55. The method of claim 54 wherein saidpolymorph form C is administered to the patient at an oral dose of fromabout 0.5 mg/kg to about 5.0 mg/kg of body weight per day
 56. Apharmaceutical composition comprising a mixture of polymorph form A andeither or both polymorph form B and polymorph form C of apharmaceutically acceptable acid addition salt of(+)-1-(3,4-dichloro)-3-azabicyclo[3.1.0]hexane.
 57. The pharmaceuticalcomposition according to claim 56 wherein the amount of polymorph form Aranges from about 10% to about 20% (by weight).
 58. The pharmaceuticalcomposition according to claim 56 wherein the amount of polymorph form Aranges from about 20% to about 35% (by weight).
 59. The pharmaceuticalcomposition according to claim 56 wherein the amount of polymorph form Aranges from about 35% to about 50% (by weight).
 60. The pharmaceuticalcomposition according to claim 56 wherein the amount of polymorph form Aranges from about 50% to about 70% (by weight).
 61. The pharmaceuticalcomposition according to claim 56 wherein the amount of polymorph form Aranges from about 70% to about 85% (by weight).
 62. The pharmaceuticalcomposition according to claim 56 wherein the amount of polymorph form Aranges from about 85% to about 95% (by weight).
 63. The pharmaceuticalcomposition according to claim 56 wherein the amount of polymorph form Aranges from about 95% to about 99% (by weight).
 64. A pharmaceuticalcomposition comprising a mixture of polymorph form B and either or bothpolymorph form A and polymorph form C of a pharmaceutically acceptableacid addition salt of (+)-1-(3,4-dichloro)-3-azabicyclo[3.1.0]hexane.65. A pharmaceutical composition comprising a mixture of polymorph formC and either or both polymorph form A and polymorph form B of apharmaceutically acceptable acid addition salt of(+)-1-(3,4-dichloro)-3-azabicyclo[3.1.0]hexane.